Melatonin Reduces Mito-Inflammation in Ischaemic Hippocampal HT22 Cells and Modulates the cGAS–STING Cytosolic DNA Sensing Pathway and FGF21 Release

: Mitochondrial dysfunction is a key event in many pathological conditions, including neurodegenerative processes. When mitochondria are damaged, they release damage-associated molecular patterns (DAMPs) that activate mito-inflammation. The present study assessed mito-inflammation after in vitro oxygen-glucose deprivation as a representation of ischaemia, followed by reoxygenation (OGD/R) of HT22 cells and modulation of the inflammatory response by melatonin. We observed that melatonin prevented mitochondrial structural damage and dysfunction caused by OGD/R. Melatonin reduced oxidative damage and preserved the enzymatic activity for complexes I, III and IV, encoded by mitochondrial DNA, which were reduced by OGD/R. No effect was observed on complex II activity encoded by nuclear DNA. The release of mtDNA into the cytosol was also prevented with a consequent reduction of the cGAS-STING pathway and IFNβ and IL-6 production. Interestingly, melatonin also increased the early release of the fibroblast growth factor-21 (FGF-21), a mitokine secreted in response to mitochondrial stress. These data indicate that melatonin reduces mito-inflammation and modulates FGF-21 release, further highlighting the key role of this molecule in preserving mitochondrial integrity in OGD/R deprivation-type ischaemic brain injury

Improved Outcome of Alternative Donor Transplantations in Patients with Myelofibrosis: From Unrelated to Haploidentical Family Donors

Abstract This is a retrospective analysis of 95 patients with myelofibrosis who were allografted between 2001 and 2014. The aims of the study were to assess whether the outcome of alternative donor grafts has improved with time and how this compares with the outcome of identical sibling grafts. Patients were studied in 2 time intervals: 2000 to 2010 (n = 58) and 2011 to 2014 (n = 37). The Dynamic International Prognostic Scoring System score was comparable in the 2 time periods, but differences in the most recent group included older age (58 versus 53 years, P = .004), more family haploidentical donors (54% versus 5%, P .0001), and the introduction of the thiotepa-fludarabine-busulfan conditioning regimen (70% of patients versus 2%, P .0001). Acute and chronic graft-versus-host disease were comparable in the 2 time periods. The 3-year transplantation-related mortality (TRM) in the 2011 to 2014 period versus the 2000 to 2010 period is 16% versus 32% ( P = .10), the relapse rate 16% versus 40% ( P = .06), and actuarial survival 70% versus 39% ( P = .08). Improved survival was most pronounced in alternative donor grafts (69% versus 21%, P = .02), compared with matched sibling grafts (72% versus 45%, P = .40). In conclusion, the outcome of allografts in patients with myelofibrosis has improved in recent years because of a reduction of both TRM and relapse. Improvement is most significant in alternative donor transplantations, with modifications in donor type and conditioning regimen

Hippocampal atrophy and white matter lesions characteristics can predict evolution to dementia in patients with vascular mild cognitive impairment

Background: Vascular mild cognitive impairment (VMCI) is a transitional condition that may evolve into Vascular Dementia(VaD). Hippocampal volume (HV) is suggested as an early marker for VaD, the role of white matter lesions (WMLs) in neurodegeneration remains debated. Objectives: Evaluate HV and WMLs as predictive markers of VaD in VMCI patients by assessing: (i)baseline differences in HV and WMLs between converters to VaD and non-converters, (ii) predictive power of HV and WMLs for VaD, (iii) associations between HV, WMLs, and cognitive decline, (iv)the role of WMLs on HV. Methods: This longitudinal multicenter study included 110 VMCI subjects (mean age:74.33 ± 6.63 years, 60males/50females) from the VMCI-Tuscany Study database. Subjects underwent brain MRI and cognitive testing, with 2-year follow-up data on VaD progression. HV and WMLs were semi-automatically segmented and measured. ANCOVA assessed group differences, while linear and logistic regression models evaluated predictive power. Results: After 2 years, 32/110 VMCI patients progressed to VaD. Converting patients had lower HV(p = 0.015) and higher lesion volumes in the posterior thalamic radiation (p = 0.046), splenium of the corpus callosum (p = 0.016), cingulate gyrus (p = 0.041), and cingulum hippocampus(p = 0.038). HV alone did not fully explain progression (p = 0.059), but combined with WMLs volume, the model was significant (p = 0.035). The best prediction model (p = 0.001) included total HV (p = 0.004) and total WMLs volume of the posterior thalamic radiation (p = 0.005) and cingulate gyrus (p = 0.005), achieving 80% precision, 81% specificity, and 74% sensitivity. Lower HV were linked to poorer performance on the Rey Auditory-Verbal Learning Test delayed recall (RAVLT) and Mini Mental State Examination (MMSE). Conclusions: HV and WMLs are significant predictors of progression from VMCI to VaD. Lower HV correlate with worse cognitive performance on RAVLT and MMSE tests

Upadacitinib effectiveness and factors associated with minimal disease activity achievement in patients with psoriatic arthritis: preliminary data of a real-life multicenter study

Background: Upadacitinib (UPA) is a selective JAK inhibitor recently approved for the treatment of psoriatic arthritis (PsA). In this post-approval study, we aimed to evaluate the effectiveness and safety of UPA over 24 weeks and identify clinical predictors of response, in a multicentric cohort of patients affected by PsA. Methods: One hundred and twenty-six patients with PsA treated with UPA were enrolled in 10 Italian centres. UPA effectiveness outcomes, such as the proportion of patients with MDA status, DAPSA remission, and low disease activity, ASDAS-CRP inactive and low disease activity, and change from baseline in DAPSA and ASDAS-CRP scores, were evaluated every 12 weeks until week 24. The proportion of DAPSA minor, moderate, and major improvement, and ASDAS clinically important improvement (CII) and major improvement (MI) were considered as well. All treatment-related adverse events were collected during the observation period. Clinical predictors of MDA response at week 24 were evaluated through multivariate analysis. Results: At baseline, 124/126 (98%) and 54/126 (43%) patients showed peripheral and axial involvement, respectively; 110 (87%) patients were intolerant or resistant to biologic DMARDs. At 24 weeks, MDA status, DAPSA remission, and ASDAS-CRP inactive disease were achieved in 47%, 23%, and 48% of patients, respectively. Minor, moderate, and major DAPSA improvement was observed in 67%, 39%, and 23%, respectively; while 65% and 35% achieved ASDAS-CRP CII and MI, respectively. The mean change from baseline was 15.9 ± 13.5 (p < 0.001) for DAPSA and 1.21 ± 0.97 (p < 0.001) for ASDAS-CRP. Thirteen patients (10%) discontinued UPA due to a lack of efficacy or non-serious adverse events. No serious adverse events were observed. Male gender (OR 2.54, 95% CI 1.03-6.25 p = 0.043), being naïve to biological DMARDs (OR 4.13, 95% CI 1.34-12.71, p = 0.013) and elevated baseline CRP (OR 2.49, 95% CI 1.02-6.12, p = 0.046) were associated with MDA response at week 24. Conclusions: This is one of the first real-life studies supporting the effectiveness of UPA and its safety profile in PsA patients. Furthermore, the study identifies predictors of MDA response to UPA treatment at 6 months

Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice’s respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Purpose: Mowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS. Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.</p

Deep Learning Modeling to Differentiate Multiple Sclerosis From MOG Antibody-Associated Disease

Background and Objectives:Multiple sclerosis (MS) is common in adults while myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is rare. Our previous machine-learning algorithm, using clinical variables, ≤6 brain lesions, and no Dawson fingers, achieved 79% accuracy, 78% sensitivity, and 80% specificity in distinguishing MOGAD from MS but lacked validation. The aim of this study was to (1) evaluate the clinical/MRI algorithm for distinguishing MS from MOGAD, (2) develop a deep learning (DL) model, (3) assess the benefit of combining both, and (4) identify key differentiators using probability attention maps (PAMs). Methods:This multicenter, retrospective, cross-sectional MAGNIMS study included scans from 19 centers. Inclusion criteria were as follows: adults with non-acute MS and MOGAD, with high-quality T2-fluid-attenuated inversion recovery and T1-weighted scans. Brain scans were scored by 2 readers to assess the performance of the clinical/MRI algorithm on the validation data set. A DL-based classifier using a ResNet-10 convolutional neural network was developed and tested on an independent validation data set. PAMs were generated by averaging correctly classified attention maps from both groups, identifying key differentiating regions. Results:We included 406 MRI scans (218 with relapsing remitting MS [RRMS], mean age: 39 years ±11, 69% F; 188 with MOGAD, age: 41 years ±14, 61% F), split into 2 data sets: a training/testing set (n = 265: 150 with RRMS, age: 39 years ±10, 72% F; 115 with MOGAD, age: 42 years ±13, 61% F) and an independent validation set (n = 141: 68 with RRMS, age: 40 years ±14, 65% F; 73 with MOGAD, age: 40 years ±15, 63% F). The clinical/MRI algorithm predicted RRMS over MOGAD with 75% accuracy (95% CI 67-82), 96% sensitivity (95% CI 88-99), and specificity 56% (95% CI 44-68) in the validation cohort. The DL model achieved 77% accuracy (95% CI 64-89), 73% sensitivity (95% CI 57-89), and 83% specificity (95% CI 65-96) in the training/testing cohort, and 70% accuracy (95% CI 63-77), 67% sensitivity (95% CI 55-79), and 73% specificity (95% CI 61-83) in the validation cohort without retraining. When combined, the classifiers reached 86% accuracy (95% CI 81-92), 84% sensitivity (95% CI 75-92), and 89% specificity (95% CI 81-96). PAMs identified key region volumes: corpus callosum (1872 mm3), left precentral gyrus (341 mm3), right thalamus (193 mm3), and right cingulate cortex (186 mm3) for identifying RRMS and brainstem (629 mm3), hippocampus (234 mm3), and parahippocampal gyrus (147 mm3) for identifying MOGAD. Discussion:Both classifiers effectively distinguished RRMS from MOGAD. The clinical/MRI model showed higher sensitivity while the DL model offered higher specificity, suggesting complementary roles. Their combination improved diagnostic accuracy, and PAMs revealed distinct damage patterns. Future prospective studies should validate these models in diverse, real-world settings. Classification of Evidence:This study provides Class III evidence that both a clinical/MRI algorithm and an MRI-based DL model accurately distinguish RRMS from MOGAD

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221